Illicit drug use is not only a major global health problem, but has also had a profoundly negative social, political, and economic impact that continues to increase in magnitude. Although treatments such as the nicotine patch or methadone have been useful in reducing addictions to smoking and opiate abuse, there are currently no such treatments for cocaine or methamphetamine addiction. In view of the magnitude of the health problem and the lack of an appropriate drug substitution therapy for addicts, research efforts have focused on the concept of developing vaccines against drugs of abuse. The hypothesis that drives this line of study is quite simple-by reducing the concentration of free drug in plasma via antibody binding, the ability of the drug to reach the brain in sufficient amounts to elicit a pleasurable, reinforcing effect would be dramatically reduced. Although progress has been made in developing candidate vaccines, these vaccines suffer from several critical weaknesses: insufficient titers of induced anti-cocaine antibodies and the need for large amounts of vaccine and large numbers of vaccinations. We propose to prepare cocaine analog: flagellin conjugates that will take advantage of the potent adjuvant effect and immunogenicity of flagellin to elicit robust T cell- dependent, antigen-specific antibody responses. Based on the results of work on flagellin- based vaccines, we fully expect that low amounts of vaccine and limited vaccinations will induce titers that are at least 10-50x higher than previously obtained with cocaine vaccines. We will immunize mice and rats and evaluate plasma titers of anti-cocaine IgG, as well as the levels of cocaine in immune and control animals following administration of the drug. In addition, we will use a range of assays to assess the effect of immunization on the pharmacological effects of cocaine in these animals, as well as the potential for immunization to limit self-administration and the development of dependence. Finally, we will assess the effect of immunization in nonhuman primates on the ability of cocaine to reach the brain. At the conclusion of the proposed studies, we expect to accomplish the following goals: 1) develop a highly efficacious cocaine analog:flagellin conjugate that elicits a robust anti-cocaine IgG response and 2) vaccine-mediated sequestering of cocaine such that minimal levels enter the brain and the pharmacological effects of cocaine are dramatically muted. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a vaccine against cocaine that elicits extremely high titers of neutralizing antibodies and that dramatically reduces the reinforcing pleasurable effects of cocaine. If successful, such a vaccine would not only have tremendous potential as a means to reduce cocaine use and addiction in American society, but would also validate the use of flagellin as an adjuvant and vaccine carrier for other drugs of abuse.